ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9730G>T (p.Val3244Phe) (rs11571831)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216607 SCV000276441 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-04 criteria provided, single submitter clinical testing
Color RCV000216607 SCV000689223 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000589199 SCV000616663 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9730G>T at the cDNA level, p.Val3244Phe (V3244F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTC>TTC). Using alternate nomenclature, this variant would be defined as BRCA2 9958G>T. This variant has been observed in at least one individual with breast cancer (Li 2017). BRCA2 Val3244Phe was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Val3244Phe occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Val3244Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589199 SCV000695267 uncertain significance not provided 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9730G>T (p.Val3244Phe) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121354 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance/likely neutral. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000467527 SCV000549739 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-07-10 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 3244 of the BRCA2 protein (p.Val3244Phe). The valine residue is weakly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs11571831, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 38263). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000031846 SCV000054454 uncertain significance Breast-ovarian cancer, familial 2 2010-06-11 no assertion criteria provided clinical testing

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